The present application claims priority under the Paris Convention to Indian patent application entitled, xe2x80x9cA Herbal Composition and Process for the Manufacture of such Composition for the Management of Gynecological Disorders,xe2x80x9d filed on Mar. 28, 2000 and assigned Indian Application Ser. No. 344/Del/2000.
The present invention is a herbal composition enriched with plant coagulate for the management of gynecological disorders and a process for the manufacture of such composition. In one embodiment, the herbal composition includes selected herbs in predetermined ratio ranges in combination with plant coagulate. The method of manufacture involves selective solvent extraction of crude herbs, in contrast to conventional aqueous extraction, to improve efficacy. The extract prepared by this method, enriched with plant coagulate, is useful in the management of Gynecological disorders and to prevent/treat anaemia due to excessive bleeding associated with menstrual disorders.
Gynecology pertains to diseases of the female, but the term is generally used for diseases related to the female genital organs. Menstrual disorders such as dysfunctional uterine bleeding, dysmenorrhoea, irregular periods and pre-menstrual syndrome are common clinical problems in Gynecology.
Dysfunctional uterine bleeding (DUB) is defined as abnormal bleeding from the uterus in the absence of organic disease of the genital tract. Bleeding that occurs at intervals less than 21 days or more than 36 days, lasts longer than 7 days, or involves blood loss greater than 80 ml is considered abnormal. Dysfunctional uterine bleeding is characterized by menorrhagia (excessively profuse or prolonged uterine bleeding occurring at regular intervals), metrorrhagia (irregular, acyclic uterine bleeding occurring at frequent intervals), menometrorrhagia (excessive uterine bleeding occurring at irregular intervals), and polymenorrhea (bleeding occurring at regular intervals of less than 21 days). Potential causes of abnormal bleeding are numerous and include, but are not limited to, menopause, pregnancy, endometrial cancer, or fibromyomata, and thus the diagnosis of DUB must be made after careful investigation to exclude these other causes (Galle et al., Postarad Med, 93(2), 73-76 (1993)). Dysfunctional uterine bleeding is divided into anovulatory and ovulatory types. In most cases DUB is associated with anovulation (Bayer et al., JAMA, 269(14), 1823-1828 (1993)). Abnormal bleeding occurs in anovulatory cycles because of oestrogen withdrawal or oestrogen breakthrough bleeding. Oestrogen breakthrough bleeding occurs when there is continuous oestrogen stimulation of the endometrium not interrupted by cyclical progesterone secretion and withdrawal.
There are two approaches for the management of Gynecological problemsxe2x80x94conservative and surgical. Conservative approach includes hormonal treatment with estrogenic or progestational agents (Bayer et al., JAMA, 269(14), 1823-1828 (1993)), nonsteroidal anti-inflammatory drugs and/or treatment with Ayurvedic preparations.
The constraints with the hormonal treatment and NSAID are tabulated (U.S. Pat. No. 5,552,416, Sep. 3, 1996; Shaw""s textbook of Gynecology, 319, 1992)
Because of the side effects of the hormones and NSAIDS, physicians are looking for alternative options for treatment with minimum side effects.
(1) Ayurvedic literature suggests the use of herbs such as Saraca indica Linn. (Ashoka) (Bhavaprakasa Nighantu, ninth edition, 500-501 (1993)), Symplocos racemosa Roxb.(Lodhra) (Bhavaprakasa Nighantu, ninth edition, 128-130 (1993)), Woodfordia fruticosa kurtz (Dhatki pushpa) (Bhavaprakasa Nighantu, ninth edition, 109-110 (1993)) etc. in the treatment of gynecological disorders.
(2) Saraca indica Linn. was studied for its uterine activity to understand its phenomenal use in gynecological conditions (Satyavati et al., Indian J Med Res, 58, 7 July, 1970).
(3) The following citations of different herbs exemplify known roles of herbs in the management of gynecological conditions.
(i) In Pradara (meno-metrorrhagia) one should take cold milk boiled with the decoction of ashoka bark. (Vrndamadhava 63.5)(Classical uses of Medicinal Plants by P. V. Sharma, 27, 1996).
(ii) Symplocos racemosa Roxb. in combination with sugar is recommended in the treatment of menorrhagia and other uterine disorders (The Wealth of India, Vol. X, 90, 1976).
(iii) Lodhra is useful in women""s diseases (Classical uses of Medicinal Plants by P. V. Sharma, 333, 1996).
(a) In the eighth month, by taking Lodhra, Pippali and honey mixed together with milk, fetal movement becomes normal (Harita-samhita.3.50.5).
(b) Lodhra and Alabu leaves in equal parts should be pounded and applied as paste in the vagina in order to treat gynecological conditions. (Bhavaprakasa.ci.70.12).
(c) Lodhrasava is a popular herbal formulation for the treatment of women""s diseases.
(iv) Woodfordia fruticosa kurtz. is used in bowel complaints and haemorrhages and is also administered in menorrhagia and seminal weakness (The Wealth of India, Vol. X, 586-587, 1976).
(v) Dhataki pushpa is used in Leucorrhoea and for conception (Classical uses of Medicinal Plants by P. V. Sharma, 204, 1996).
(a) Powder of Dhataki or Amlaki in an amoutn of 10 gm mixed with profuse honey should be used in Leucorrhoea (Vrandamadhava 63.4).
(b) Nilotpala mixed with dhataki flowers and honey is used in the morning hours to ensure conception (Gadanigraha 6.59).
(vi) Mangifera indica (Amrasthi) is used in slackness of vagina (Classical uses of Medicinal Plants by P. V. Sharma, 40, 1996).
(a) Paste is made from mango seed (Kernel), honey and camphor and applied to vagina in order to make the vagina contracted and firm. (Sarangadhara-samhita.3.11.11)
(4) Ashokarishta, a classical ayurvedic fermented product has been used to treat menstrual disorders. (Bhaishajya Ratnavali, 704, 1988).
Based on the long history of using herbs as cited above, many Ayurvedic classical and proprietary formulations contain these herbs for the treatment of gynecological problems.
There are limitations, however, to using these formulations and, therefore, there exists room to improve upon them. Below is a description of limitations present in the prior art.
(1) First, it is conventional practice to perform an aqueous extraction of crude herbs for the manufacture of Ayurvedic preparations. This, however, often results in the incomplete extraction of actives present in the plants, due to their poor solubility in water. For instance, commonly occurring plant flavonoids have estrogenic activity (Miksicek R J, Mol Pharmacol 1993, Jul.;44(1): 37-43). Even the herbs containing flavonoids are traditionally extracted with water in the manufacture of many Ayurvedic preparations. This results in lesser flavonoid content in the extract and hence is expected to show less activity.
(2) Second, the patients suffering from menstrual disorders are likely to develop anemia due to excessive bleeding. Commonly, there is a need to treat both the problems simultaneously. Unfortunately, most of the Ayurvedic preparations are designed to tackle menstrual problems ignoring the prophylactic treatment for anemia.
Plant coagulate mainly finds its application as a food supplement. The nutritional profile of plant coagulate includes protein, fat, carbohydrates, vitamins such as carotene, niacin, etc. and minerals such as calcium, phosphorous, magnesium, potassium, zinc, copper and iron.
Several publications claim the successful use of Plant coagulate in the management of malnutrition, especially in children (Shah F H et al., Qual Plant Foods Hum Nutr., 30, 245;1981; Mathur. B et al., Recent Advances in Nutriology, Volume I, 54A.).
Mathur. B et al., The Ind Nutr Diete., 26, 267; 1989, has shown the usefulness of Plant coagulate in improving hemoglobin levels in children.
(3) Third, the dose of classical liquid formulations is high and palatability is less due to an astringent taste and insitu alcohol.
The present invention discloses a novel herbal composition and a process to make an herbal extract to enhance the efficacy in treating gynecological disorders, in particular menstrual disorders. The process involves combining aqueous and organic solvent extracts of selective plants contained in the composition to perform better than conventional aqueous extract.
In one embodiment of the invention, twelve herbs are extracted with water and three herbs, which are rich in flavonoids, are extracted with 75% alcohol to get maximum flavonoid content and the extracts are then combined. The combined extract is compared with the conventional aqueous extract for their Uterotonic activity.
The combined extract obtained by this process is enriched with plant coagulate prepared by a heat coagulation method to make an herbal composition for the simultaneous treatment of gynecological conditions and resultant anemia due to excessive bleeding.
An effective amount of the herbal extract enriched with plant coagulate and conventional extract are formulated into a suitable dosage form and the improved efficacy of the herbal extract prepared by this novel process is proven by a clinical study.
The present invention includes the preparation of herbal extracts by selective solvent extraction of crude herbs to improve the efficacy of the extract. The herbal extract prepared by this method is enriched with plant coagulate to make an herbal composition for the treatment of gynecological disorders.
In one embodiment, the activity of herbal extracts in the treatment of gynecological disorders is observed when the following active ingredients, both individually and in varying combinations, optionally present in the following ranges, or in other ranges that achieve the desired result.
Below is one example of the steps that may be followed to manufacture the herbal compositions of the present invention. One of ordinary skill in the art would understand that certain substitutions may be made for any traditional laboratory techniques described below.
Step I: Some of the herbs in the composition are preferably Saraca indica, Emblica officinalis, Terminalia chebula, Terminalia belerica, Zingiber officinale, Cyperus rotundus, Pterocarous santalimus, Beriberis aristata, Cuminum cyminum, Adhatoda vasika, Nelumba nucifera and Piper longum. They are coarsely powdered in a suitable cutting mill. The coarse powder is extracted with a high polar solvent preferably with sufficient water (approx. 4-10 times the quantity of powder) using suitable equipment, preferably in a open boiling pan. Once the extraction is over, the decoction is filtered through suitable filtering medium and collected in a storage tank. The herbs are again extracted with water (approx. 3-8 times) for a second time and the filtrate is collected into the storage tank. The total filtrate is concentrated to dry powder using suitable equipment like concentration pan, falling film evaporator, at atmospheric pressure or under vacuum, and/or tray drier, or by spray drying process. The extract may have a moisture content of 3-8%w/w.
Step II: Some of the herbs in the composition, preferably Symplocos racemosa, Woodfordia fruticosa and Mangifera indica, are coarsely powdered using a cutting mill. In order to effect the extraction procedure, the coarse powder is extracted in a blended solvent that includes water and an organic solvent, preferably alcohol in a defined ratio varying between 1:9 and 9:1 in a suitable apparatus. The extract obtained is concentrated in suitable equipment at atmospheric pressure or under vacuum.
Step III: The dry extracts obtained in step I and step II are mixed well. The combined extract was studied for the Uterotonic activity in comparison to conventional aqueous extract.
Step IV: Plant coagulate claimed to be useful in the treatment of iron deficiency conditions is added to the herbal extract prepared by the novel method to manage anemia associated with menstrual disorders. Plant coagulate may be prepared from any plant source and/or combined plant source. In this study, plant coagulate is prepared from any single plant or combination of two or more plants comprising mainly green leaf matter, preferably among spinach (Spinacia oleracea), Amaranth (Amaranthus spp.), Berseem (Trifolium alaxandrum) and Cowpea (Vigna sinensiss) by a suitable method, preferably heat coagulation.
The herbal composition comprising the herbal extract prepared by the novel process and Plant coagulate is formulated into a suitable dosage form. The increased efficacy of these formulations against conventional aqueous extract formulation, in the treatment of gynecological disorders and the resultant anemia due to excessive bleeding has been confirmed by a clinical study.
In one aspect according to the present invention, the active composition according to the present invention is formulated preferably in admixture with a pharmaceutically acceptable carrier. In general, it is preferable to administer the pharmaceutical composition in orally administrable form, but formulations may be administered via parenteral, intravenous, intramuscular, transdermal, buccal, subcutaneous, suppository or other route. Intravenous and intramuscular formulations are preferably administered in sterile saline. One of ordinary skill in the art may modify the formulation within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising its therapeutic activity. In particular, a modification of a desired composition to render it more soluble in water or other vehicle, for example, may be easily accomplished by routine modification (salt formulation, esterification, etc.).
The amount of active composition included within therapeutically active formulations, according to the present invention, is an effective amount for treating gynecological conditions. For purposes of the present invention, a prophylactically or preventively effective amount of the compositions, according to the present invention, falls within the same concentration range for therapeutically effective amount and is usually the same as a therapeutically effective amount.
Administration of the active composition may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D., B.I.D., etc.) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration. Enteric-coated oral tablets may also be used to enhance bioavailability and stability of the composition from an oral route of administration. The most effective dosage form will depend upon the pharmacokinetics of the particular agent chosen, as well as the severity of the condition in the patient. Oral dosage forms are particularly preferred, because of ease of administration and prospective favorable patient compliance.
To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of the herein described composition according to the present invention is preferably mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. If desired, the tablets or capsules may be enteric-coated for sustained release by standard techniques. The use of these dosage forms may significantly impact the bioavailability of the composition in the patient.
For parenteral formulations, the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients, including those which aid dispersion, also may be included. Where sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
The invention will now be described with reference to the accompanying examples which should not be construed to limit the scope of the invention: